According to the World Health Organization, 4.8 million people were newly infected with HIV in 2003[unreadable] bringing the total number to some 37.8 million people who are living with HIV. Since the first cases of AIDS[unreadable] were identified in 1981, over 20 million have died by this disease. In spite of remarkable medical advances,[unreadable] HIV-1 infections continue to increase. Our goal is to identify drugs against a novel and unexploited target[unreadable] for the treatment of AIDS. The human immunodeficiency virus type 1 (HIV-1), the causative agent of AIDS,[unreadable] is a complex retrovirus that encodes six regulatory proteins, including Vif that is essential for viral replication[unreadable] in vivo. Since there are no known cellular homologs of HIV-1 Vif, this protein represents an extremely[unreadable] attractive, yet unrealized, target for antiviral intervention. Therefore, we propose to identify lead inhibitors of[unreadable] HIV-1 Vif function. Our specific aims are as follows: (1) Identification of Vif inhibitors. Experiments are[unreadable] proposed to develop highly robust and reproducible fluorescence-based assays to monitor HIV-1 Vif[unreadable] function in cellular environment. High throughput screening assays will be employed to identify small[unreadable] molecule inhibitors that can target Vif-APOBEC3G interactions. (2) Structure activity relation studies and[unreadable] validation of lead compounds. Experiments are proposed to characterize the efficacy and specificity of the[unreadable] compounds identified as Vif inhibitors from initial screening experiments. Selected compounds will be tested[unreadable] for their anti-HIV Vif activities in both permissive and non-permissive cells (Project #2). Antiviral activities of[unreadable] selected Vif antagonists against clinical HIV-1 isolates will be analyzed and the safety and stability profiles[unreadable] of these compounds will be determined (core B). Consequences of Vif antagonist's activities in chronically[unreadable] infected macaques will be investigated in project #3. As a support to pharmacology studies (project #3 and[unreadable] core B), we will measure the drug concentrations in plasma of drug treated animals. Based on the activity,[unreadable] stability, and toxicity data (projects 2 and 3, and core B), new compounds will be synthesized to improve the[unreadable] potency and selectivity of lead structures. (3) Mechanism(s) of Vif inhibition. Experiments will be performed[unreadable] to understand the mechanism of Vif inhibitors at molecular level.